Biology subjects

Adamberg, K.

Publications and source records attributed to Adamberg, K..

3 recordsLinked to original sources

bioRxiv2023

A reproducible enteric phage community improves blood glucose regulation in an obesity mouse model

Metabolic syndrome encompasses amongst other conditions like obesity, type-2 diabetes, and metabolic dysfunction associated fatty liver disease (MAFLD), which are all associated with gut microbiome (GM) dysbiosis. Fecal microbiota transplantation (FMT) has been explored to treat metabolic syndrome by restoring the GM. FMT is generally safe, but motivated by case reports, accidental transfer of pathogenic bacteria remains a concern. As a safer alternative, fecal virome transplantation (FVT, sterile-filtrated feces) has the advantage over FMT in that mainly bacteriophages are transferred and FVT from lean male donors has shown promise in alleviating the metabolic effects of a high-fat diet in a preclinical mouse study. However, FVT still carries the risk of eukaryotic viral infections. To address this, we here apply recently developed modification methodologies to inactivate or remove the eukaryotic viral component of FVT while maintaining an active enteric bacteriophage community. Modified FVTs were compared with unmodified FVT and saline in an animal model of diet-induced obesity using male C57BL/6N mice. In contrast to the obese control group, mice administered a modified FVT, nearly depleted from eukaryotic viruses (0.1%), exhibited enhanced blood glucose clearance, although without a concurrent reduction in weight gain. The unmodified FVT improved liver pathology and reduced the proportions of immune cells in the adipose tissue with a non-uniform response. GM analysis suggested that bacteriophage-mediated GM modulation had influenced these outcomes. When optimized, this may pave the way for developing safe bacteriophage-based therapies targeting metabolic syndrome through GM restoration.

microbiology↗

bioRxiv2023

Development of safe and effective bacteriophage-mediated therapies against C. difficile infections a proof-of-concept preclinical study

BackgroundFecal microbiota transplantation (FMT) and fecal virome transplantation (FVT, sterile filtrated donor feces) have been effective in treating recurrent Clostridioides difficile infections, possibly through bacteriophage-mediated modulation of the gut microbiome. However, challenges like donor variability, costly screening, coupled with concerns over pathogen transfer (incl. eukaryotic viruses) with FMT or FVT hinders their wider clinical application in treating less acute diseases. MethodsTo overcome these challenges, we developed methods to broaden FVTs clinical application while maintaining efficacy and increasing safety. Specifically, we employed the following approaches: 1) Chemostat-fermentation to reproduce the bacteriophage FVT donor component and remove eukaryotic viruses (FVT-ChP), 2) solvent-detergent treatment to inactivate enveloped viruses (FVT-SDT), and 3) pyronin-Y treatment to inhibit RNA-virus replication (FVT-PyT). We assessed the efficacy of these processed FVTs in a C. difficile infection mouse model and compared them with untreated FVT (FVT-UnT), FMT, and saline. ResultsFVT-SDT, FVT-UnT, and FVT-ChP reduced the incidence of mice reaching the humane endpoint (0/8, 2/7, and 3/8, respectively) compared to the FMT, FVT-PyT, and saline control (5/8, 7/8, and 5/7, respectively) and significantly reduced the load of colonizing C. difficile cells and toxin A/B levels. There was a potential elimination of C. difficile colonization, with 7 out of 8 mice treated with FVT-SDT testing negative with qPCR. In contrast, all other treatments exhibited the continued presence of C. difficile. Moreover, the results were supported by changes in the gut microbiome profiles, cecal cytokine levels and histopathological findings. Assessment of viral engraftment following FMT/FVT treatment and host-phage correlations analysis suggested that transfer of phages likely were an important contributing factor associated with treatment efficacy. ConclusionsThis proof-of-concept study show that specific modifications to FVT hold promise in addressing challenges related to donor variability and infection risks. Two strategies lead to treatments significantly limiting C. difficile colonization in mice, with solvent/detergent treatment and chemostat-propagation emerging as promising approaches.

microbiology↗

bioRxiv2023

Reproducible chemostat cultures to eliminate eukaryotic viruses from fecal transplant material

The effect of fecal microbiota transplantation (FMT) on various gut-related diseases is intensively investigated in clinical trials. In addition to bacteria, the gut microbiome also contains eukaryotic, archaeal, and bacterial viruses (bacteriophages, in short phages), which collectively is referred to as the gut virome. Application of FMT in clinical settings is associated with a potential risk for the recipient of transferring infectious eukaryotic viruses or bacteria, despite strict screening procedures for the donor material. A safer and more targeted method to modulate the gut microbiota is therefore needed to extend the application width of FMT. Emerging evidence suggests that gut phages play a key role in maintaining a balanced gut microbiome as well as in FMT efficacy. Thus, a phageome from a cultured fecal donor microbiome may be a more efficient alternative to modulate the gut bacteriome than FMT. Here, we analyzed the dynamic changes of the viromes of mice cecal and human fecal matter inoculated chemostat cultures. Sequencing results showed that the relative abundance of eukaryotic viruses remarkably decreased during continuous cultivation, likely due to the lack of eukaryotic hosts. The corresponding phageome profiles showed dilution rate dependency, a reproducibility between biological replicates, and maintained high diversity of phages although being different from the inoculum phageome. This proof-of-concept study may constitute the first step of developing therapeutic tools to target a broad spectrum of gut-related diseases and thereby replacing FMT with a safer phage-mediated therapy.

microbiology↗